The long-term goal of this project is to elucidate the mechanisms by which statins modify the risk of Alzheimer disease (AD). Statins are a class of cholesterol-lowering drugs that have been used successfully to prevent cardiovascular diseases. Recently, retrospective studies have shown an apparent reduction of risk for Alzheimer's disease in people receiving statins but not other classes of cholesterol-lowering drugs, suggesting protective effects of statins beyond cholesterol lowering. The powerful cholesterol-lowering effect of statins, however, has made it difficult to distinguish between the cholesterol and non-cholesterol effects of statins, as both mechanisms may affect the same pathogenic mechanisms. The protective effect of statins on Alzheimer's disease has been attributed to their ability to modulate the processing of amyloid-beta precursor protein leading to a decreased production of amyloid-p protein. In a preliminary study using a mouse model of Alzheimer's disease, however, a commonly used statin drug (simvastatin) enhances learning and memory independent of amyloid reduction. Therefore, the working hypothesis of this proposal is that statins modulate AD-related behavior and pathology beyond cholesterol lowering and amyloid reduction. This hypothesis will be tested by two Specific Aims: 1) to determine the efficacy of statins (simvastatin and pravastatin) and a non-statin cholesterol-lowering drug (ezetimibe) in modulating AD-type behavior and pathology in a mouse model of Alzheimer's disease. Simvastatin and pravastatin are chosen to represent the extremes of the lipophilicity spectrum of statins. Ezetimibe, a newly approved drug, is a potent, selective cholesterol absorption inhibitor. Because ezetimibe lowers plasma cholesterol but through a completely different mechanism from that of statins, it is an ideal drug for comparison with statins; 2) to determine if statins ameliorate AD-type behavior and pathology in a newly developed AD mouse model where it has no cholesterol-lowering effects. In this model, human-like hypercholesterolemia induced by the low-density lipoprotein receptor deficiency cannot be normalized by statin treatment. Therefore, using this unique mouse model, cholesterol-independent effects of statins on AD-type behavior and pathology will be distinguished from their cholesterol-lowering effects. Results of this study will help to dissect the pleiotropic effects of statins on Alzheimer's disease. They will also provide a starting point for future studies on elucidating the cellular and molecular mechanisms by which statins exert their neurobiological effects so that novel therapies may be developed to fight against Alzheimer's disease.